Background/Purpose:  We have recently studied a group of patients with a prominent interferon (IFN) signature in the blood, distinct from IL-1 mediated autoinflammatory diseases. Six patients with de novo gain of function mutations in TMEM173, which encodes STimulator of Interferon Genes (STING), presented with early onset systemic inflammation, vasculopathy/vasculitis, and pulmonary inflammation. STING is an adaptor molecule for cytosolic DNA sensing pathway, which leads to IFNb production.  The identification of an IFN activating mutation allows us to examine the cellular origin of the IFN and the IFN response signature in patients’ cells.

Methods: Patients alive (n=4) were evaluated clinically and immunologically.  STING ligand cGAMP was used to assess its function in stimulation assays in patients’ and controls’ Peripheral Blood Mononuclear Cells (PBMCs), fibroblasts and endothelial cells. Transfection studies of STING wildtype or mutant constructs in HEK293T cells were performed and IFNb transcription in patient peripheral blood cell subsets, fibroblasts, and healthy control endothelial cells were assessed.

Results: Whole blood transcriptional profiling by RNA_seq showed significant upregulation of IFN regulated genes compared with healthy controls.  Constitutively increased transcription of IFNβ and other downstream targets of STING in patient PBMCs indicate constitutive STING/IFN pathway activation. qRTPCR analysis of RNA extracted from flow cytometer sorted cells indicates that monocytes produce by far the highest level IFNb. Transcriptional analysis by RNA_seq suggests that the STING/IFN pathway was also constitutively activated in patient fibroblasts. When stimulated with STING ligand cGAMP, patients’ fibroblasts are more sensitive and have exaggerated transcription of IFNβ but not IL-1, IL-6 and TNF. STING is expressed in endothelial cells (EC) and in vitroSTING pathway stimulation leads to EC activation and damage. 

Conclusion: STING-Associated Vasculopathy with onset in Infancy (SAVI) is a novel autoinflammatory disease caused by de novo gain of function mutations in TMEM173, which leads to constitutive STING activation and elevated IFNβ secretion. The identification of a mutation in the IFN pathway suggests the use of therapeutic agents blocking this pathway and allows us to study the cellular origin and the organ manifestations of the inflammation.

---

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigation-of-the-stinginterferon-pathway-activation-in-a-novel-vasculopathy-and-pulmonary-syndrome/